This proposal addresses the growing clinical need in dentistry and orthopaedics for materials that enable rapid osseointegration and earlier loading times for implants in bone that has been compromised by trauma or disease. 38 million US adults will have no natural teeth by 2020. Implant-supported dentures significantly improve quality of life in comparison to removable dentures, but many denture patients experience considerable bone loss, risking exposing the mandibular nerve during surgery and limiting implant placement. The aging population has an increased need for technologies that provide predictable implant osseointegration in orthopaedic sites (e.g. spine). Medical treatment for metabolic bone diseases like osteoporosis improve implant success, but many patients are not treated with these drugs. Osteoinductive agents like BMPs can improve clinical outcomes, but these technologies are expensive, can have negative side effects, and for some applications are contra-indicated. Our goal is to exploit the physical surface properties of dental and orthopaedic implants to generate new bone in patients lacking sufficient supporting bone without relying on pharmacologic interventions. Our work has shown that the microscale and nanoscale properties of 2D titanium (Ti) and Ti-alloy surfaces are sufficient to drive osteoblast differentiation of multipotent mesenchymal stem cells (MSCs) in vitro and increase the rate of new bone formation in vivo in animals and patients, improving osseointegration and implant stability. Additive manufacturing (AM) makes it possible to design-patient specific implants, but the complex geometries that are needed make modifications to interior surfaces of 3D constructs difficult to achieve. To overcome this technology limitation, we will develop our novel magnesio(calcio)thermic [M(C)T] process for generating osteogenic nanostructure on both exterior and interior surfaces of 3D AM- derived Ti-6Al-4V implants. We will: (1) Determine the mechanism(s) of the M(C)T process controlling the surface nanostructure and use this understanding to tailor nanoscale surface features for enhanced osteoblast differentiation on AM-derived 3D implants; (2) Determine the mechanisms that mediate the differential effects of surface design features on planar cell polarity and MSC commitment to an osteoblast lineage fate (i.e., obligatory change in shape from flattened MSCs, which can migrate, adhere to the implant, and proliferate, to columnar secretory osteoblasts, which synthesize and mineralize bone matrix); and (3) Assess how changes in surface design impact bone formation and remodeling in vitro by understanding how MSCs modulate osteoclast activity and in vivo using aged male and female rats to assess any sex differences, estrogen- deficient rats as a model of compromised bone health, and rabbit femurs as a model of function under load- bearing conditions. Our studies take advantage of the investigative team's skills in cell and molecular biology, experimental pathology, material science, non-destructive testing and mechanical engineering.